Induction of Autophagy in Tumors through Selective Inhibition of Sphingosine Kinase-2

Current cancer chemotherapy targets critical pathways involved in proliferation and induction of apoptosis. Unfortunately, cancer cells often acquire resistance to agents that induce apoptosis, promoting exploration of alternate cell death pathways as targets for cancer therapy. Sphingolipids are known to regulate cell signaling, proliferation, apoptosis, and autophagy. Beljanski et al. demonstrate that selective inhibition of sphingosine kinase-2 by ABC294640 [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide] induces nonapoptotic cell death in cancer cells. In vitro in cell culture and in vivo in tumors, ABC294640 induced the characteristic markers of autophagy, LC3 cleavage, and formation of autophagosomes but did not increase markers of apoptosis. An inhibitor of autophagy, 3-methyladenine, switched the mechanism of cell death to apoptosis at higher doses of ABC294640, suggesting that induction of autophagy was the dominant mechanism of cell killing. ABC294640 promotes nonapoptotic cell death through the induction of autophagy in cancer cells, and the results of this study suggest that ABC294640 may effectively complement other cancer therapies that induce apoptosis.